We are pursuing our studies of oncogene involvement in neoplastic transformation and in cellular differentiation. Toward this goal, we have analyzed in vitro transformation of cell cultures and alterations of proto-oncogenes in animal and human tumors. Transformation of embryo cells in vitro by MH2 virus has been used as a model system for understanding the differential functions of the two oncogenes contained in this virus (v-mht and v-myc). A complete MH2 provirus containing all the LTR regulatory elements has been constructed by molecular genetics techniques. This provirus (L5-MH2) is now efficiently used in transfections of chick embryo fibroblasts for the production of an infectious transforming virus. Deletion mutants have been obtained from L5-MH2 which contain one oncogene only (either v-mht or v-myc). Their differential effects on chick embryo fibroblasts in vitro are an interesting correlate of the in vivo tumorigenicity of the MC-29 family of viruses. Three human proto-oncogenes homologous to avian retroviral oncogenes have been studied in animal and human tumors. While no alterations have been detected so far in the human c-mht structure, interesting abnormalities in c-myc and c-ets appear to be present in animal and human neoplasias. We have discovered amplification of c-myc in a mouse lymphoma and in a human neuroectodermal tumor. In both cases, c-myc amplification might be correlated with tumor progression more than with the onset of the disease. Alterations of the c-ets proto-oncogene might be even more interesting because of the peculiar association of viral ets with myeloid and erythroid leukemias. Rearrangements and amplification of c-ets have been discovered in human leukemias.